Small molecules useful in the treatment of inflammatory disease

ABSTRACT

Novel compounds of the formula I                    
     which are useful for treating or preventing inflammatory and immune cell-mediated diseases. Exemplary compounds are: 
     5-(R)-(4-bromobenzyl)-3-(3-chloro-5-nitrophenyl)-5-methylimidazoline-2,4-dione; and, 
     5-(R)-(4-bromobenzyl)-3-(3-chloro-5-cyanophenyl)-5-methylimidazoline-2,4-dione.

RELATED APPLICATIONS

The benefit of prior provisional application serial No. 60/144,893,filed on Jul. 21, 1999, is hereby claimed.

FIELD OF THE INVENTION

The present invention relates generally to a series of novel smallmolecules, their synthesis and their use in the treatment ofinflammatory disease.

BACKGROUND OF THE INVENTION

Research spanning the last decade has helped to elucidate the molecularevents attending cell-cell interactions in the body, especially thoseevents involved in the movement and activation of cells in the immunesystem. See generally, Springer, T. Nature, 1990, 346, 425-434. Cellsurface proteins, and especially the Cellular Adhesion Molecules(“CAMs”) and “Leukointegrins”, including LFA-1, MAC-1 and gp150.95(referred to in WHO nomenclature as CD18/CD11a, CD 18/CD11b, andCD18/CD11c, respectively) have correspondingly been the subject ofpharmaceutical research and development having as its goal theintervention in the processes of leukocyte extravasation to sites ofinjury and leukocyte movement to distinct targets. For example, it ispresently believed that prior to the leukocyte extravasation, which is amandatory component of the inflammatory response, activation ofintegrins constitutively expressed on leukocytes occurs and is followedby a tight ligand/receptor interaction between integrins (e.g., LFA-1)and one or several distinct intercellular adhesion molecules (ICAMS)designated ICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on bloodvessel endothelial cell surfaces and on other leukocytes. Theinteraction of the CAMs with the Leukointegrins is a vital step in thenormal functioning of the immune system. Immune processes such asantigen presentation, T-cell mediated cytotoxicity and leukocyteextravasation all require cellular adhesion mediated by ICAMsinteracting with the Leukointegrins. See generally Kishimoto, T. K.;Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.;Springer, T. Current Biology, 1994, 4, 506-532.

A group of individuals has been identified which lack the appropriateexpression of Leukointegrins, a condition termed “Leukocyte AdhesionDeficiency” (Anderson, D. C.; et al., Fed. Proc. 1985, 44, 2671-2677 andAnderson, D. C.; et al., J. Infect. Dis. 1985, 152, 668-689). Theseindividuals are unable to mount a normal inflammatory and/or immuneresponse(s) due to an inability of their cells to adhere to cellularsubstrates. These data show that immune reactions are mitigated whenlymphocytes are unable to adhere in a normal fashion due to the lack offunctional adhesion molecules of the CD18 family. By virtue of the factthat LAD patients who lack CD18 cannot mount an inflammatory response,it is believed that antagonism of CD18, CD11/ICAM interactions will alsoinhibit an inflammatory response.

It has been demonstrated that the antagonism of the interaction betweenthe CAMs and the Leukointegrins can be realized by agents directedagainst either component. Specifically, blocking of the CAMs, such asfor example ICAM-1, or the Leukointegrins, such as for example LFA-1, byantibodies directed against either or both of these moleculeseffectively inhibits inflammatory responses. In vitro models ofinflammation and immune response inhibited by antibodies to CAMs orLeukointegrins include antigen or mitogen-induced lymphocyteproliferation, homotypic aggregation of lymphocytes, T-cell mediatedcytolysis and antigen-specific induced tolerance. The relevance of thein vitro studies are supported by in vivo studies with antibodiesdirected against ICAM-1 or LFA-1. For example, antibodies directedagainst LFA-1 can prevent thyroid graft rejection and prolong heartallograft survival in mice (Gorski, A.; Immunology Today, 1994, 15,251-255). Of greater significance, antibodies directed against ICAM-1have shown efficacy in vivo as anti-inflammatory agents in humandiseases such as renal allograft rejection and rheumatoid arthritis(Rothlein, R. R.; Scharschmidt, L., in: Adhesion Molecules; Wegner, C.D., Ed.; 1994, 1-38, Cosimi, C. B.; et al., J. Immunol. 1990, 144,4604-4612 and Kavanaugh, A.; et al., Arthritis Rheum. 1994, 37,992-1004) and antibodies directed against LFA-1 have demonstratedimmunosuppressive effects in bone marrow transplantation and in theprevention of early rejection of renal allografts (Fischer, A.; et al.,Lancet, 1989, 2, 1058-1060 and Le Mauff, B.; et al., Transplantation,1991, 52, 291-295).

It has also been demonstrated that a recombinant soluble form of ICAM-1can act as an inhibitor of the ICAM-1 interaction with LFA-1. SolubleICAM-1 acts as a direct antagonist of CD18,CD11/ICAM-1 interactions oncells and shows inhibitory activity in in vitro models of immuneresponse such as the human mixed lymphocyte response, cytotoxic T cellresponses and T cell proliferation from diabetic patients in response toislet cells (Becker, J. C.; et al, J. Immunol. 1993, 151, 7224 and Roep,B. O.; et al, Lancet, 1994, 343, 1590).

Thus, the prior art has demonstrated that large protein molecules whichantagonize the binding of the CAMs to the Leukointegrins havetherapeutic potential in mitigating inflammatory and immunologicalresponses often associated with the pathogenesis of many autoimmune orinflammatory diseases. However proteins have significant deficiencies astherapeutic agents, including the inability to be delivered orally andpotential immunoreactivity which limits the utility of theses moleculesfor chronic administration. Furthermore, protein-based therapeutics aregenerally expensive to produce.

Several small molecules have been described in the literature whichaffect the interaction of CAMs and Leukointegrins. A natural productisolated from the root of Trichilia rubra was found to be inhibitory inan in vitro cell binding assay (Musza, L. L.; et al., Tetrahedron, 1994,50, 11369-11378). One series of molecules (Boschelli, D. H.; et al., J.Med. Chem. 1994, 37, 717 and Boschelli, D. H.; et al., J. Med. Chem .1995, 38, 4597-4614) was found to be orally active in a reverse passiveArthus reaction, an induced model of inflammation that is characterizedby neutrophil accumulation (Chang, Y. H.; et al., Eur. J. Pharmacol.1992, 69, 155-164). Another series of molecules was also found to beorally active in a delayed type hypersensitivity reaction in rats(Sanfilippo, P. J.; et al, J. Med. Chem. 1995, 38, 1057-1059). All ofthese molecules appear to act nonspecifically, either by inhibiting thetranscription of ICAM-1 along with other proteins or act intracellularlyto inhibit the activation of the Leukointegrins by an unknown mechanism.None of the molecules directly antagonize the interaction of the CAMswith the Leukointegrins. Due to lack of potency, lack of selectivity andlack of a specific mechanism of action, the described small moleculesare not likely to be satisfactory for therapeutic use.

It follows that small molecules having the similar ability as largeprotein molecules to directly and selectively antagonize the binding ofthe CAMs to the Leukointegrins would make preferable therapeutic agents.WO9839303 discloses a class of small molecule inhibitors of theinteraction of LFA-1 and ICAM-1. WO9911258 discloses that the fungalmetabolite mevinolin and derivatives bind to LFA-1 and disrupt theinteraction of LFA-1 and ICAM-1.

SUMMARY OF THE INVENTION

A first aspect of the invention comprises a method for treating orpreventing inflammatory and immune cell-mediated diseases by theadministration of certain novel small molecules. These compounds act byinhibiting the interaction of cellular adhesion molecules, specificallyby antagonizing the binding of human intercellular adhesion molecules(including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especiallyCD18/CD11a). A second aspect of the invention comprises novel smallmolecules having the above-noted therapeutic activities. A third aspectof the invention comprises methods for making these novel compounds. Afinal aspect of the invention comprises pharmaceutical compositionscomprising the above-mentioned compounds suitable for the prevention ortreatment of inflammatory and immune cell-mediated conditions.

DETAILED DESCRIPTION OF THE INVENTION

The invention comprises compounds of the formula I

wherein:

Y is an oxygen or sulfur atom;

Z is an oxygen or sulfur atom;

X is a divalent group of the formula >CHR¹, >NR¹, >CHSO₂R¹, or >NSO₂R¹,or an oxygen or sulfur atom,

wherein R¹ is:

(A) a hydrogen atom,

(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with:

(i) halogen,

(ii) oxo,

(iii) aryl, which is selected from the class consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,

 wherein one or more hydrogen atoms of said aryl group may be optionallyand independently replaced with:

(a) alkyl of 1 to 3 carbon atoms,

(b) —COOH,

(c) —SO₂OH,

(d) —PO(OH)₂,

(e) a group of the formula —COOR⁷, wherein R⁷ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(f) a group of the formula —NR⁸R⁹, wherein R⁸ and R⁹ are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁸ andR⁹ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

(g) a group of the formula —CONR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are eachindependently a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁰ and R¹¹ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring,

(h) a group of the formula —OR^(12a), wherein R^(12a) is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

(i) a group of the formula —SR^(12b), wherein R^(12b) is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

(j) cyano, or

(k) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹³, R¹⁴ and R¹⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring,

(iv) a group of the formula —COOR¹⁶, wherein R¹⁶ is straight or branchedalkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,

(v) cyano,

(vi) a group of the formula —CONR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are each,independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁷ and R¹⁸ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring,

(vii) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, oran alkyl or acyl group of 1 to 7 carbon atoms,

(viii) a group of the formula —SR²⁰, wherein R²⁰ is a hydrogen atom, oran alkyl or acyl group of 1 to 7 carbon atoms,

(ix) a group of the formula —NR²¹R²², wherein R²¹ and R²² are each,independently,

(a) a hydrogen atom,

(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbonatoms,

(c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or 2, or

(d) a group of the formula —(CH₂)_(n)COOR²³, wherein n is 0, 1 or 2,wherein R²³ is straight or branched allyl of 1 to 6 carbon atoms,

 or wherein R²¹ and R²² constitute a saturated hydrocarbon bridge of 3to 5 carbon atoms which together with the nitrogen atom between themform a heterocyclic ring, or

(x) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is a chlorine,bromine or iodine counterion,

(C) a branched or unbranched carboxylic acid group of 3 to 6 carbonatoms,

(D) a branched or unbranched phosphonic acid group of 2 to 6 carbonatoms,

(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,

(F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and

 R²⁷, R²⁸ and R²⁹ are each, independently, a hydrogen atom or alkyl of 1to 3 carbon atoms, and wherein two of R²⁷, R²⁸ and R²⁹ may additionallyconstitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom(s) between them form a heterocyclicring,

(G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6, and

 R³⁰, R³¹, R³² and R³³ are each, independently, a hydrogen atom or alkylof 1 to 3 carbon atoms, and wherein two of R³⁰, R³¹, R³² and R³³ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring,

(H) piperidyl, wherein the nitrogen atom of said group is optionallysubstituted with:

(i) alkyl of 1 to 3 carbon atoms,

(ii) a carboxylic ester group of 2 to 7 carbon atoms,

(iii) a carboxylic acid group of 2 to 5 carbon atoms,

(iv) a phosphonic acid group of 1 to 6 carbon atoms, or

(v) a sulfonic acid groups of 1 to 6 carbon atoms, or

(I) aryl which is selected from the class consisting of phenyl,naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl,oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl,indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,

 wherein one or more hydrogen atoms of said aryl group may be optionallyand independently replaced with:

(i) alkyl of 1 to 3 carbon atoms,

(ii) —COOH,

(iii) —SO₂OH,

(iv) —PO(OH)₂,

(v) a group of the formula —COOR⁷, wherein R⁷ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(vi) a group of the formula —NR⁸R⁹, wherein R⁸ and R⁹ are each,independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁸ andR⁹ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

(vii) a group of the formula —CONR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each,independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁰ and R¹¹ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring,

(viii) a group of the formula —OR^(12a), wherein R^(12a) is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

(ix) a group of the formula —SR^(12b), wherein R^(12b) is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

(x) cyano, or

(xi) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and wherein two of R¹³, R¹⁴ and R¹⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring;

R² is:

(A) a hydrogen atom, or

(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of3 to 5 carbon atoms wherein said alkyl or cycloalkyl group mayoptionally be substituted with:

(i) a group of the formula —OR³⁴, wherein R³⁴ is a hydrogen atom, or analkyl or acyl group of 1 to 7 carbon atoms, or

(ii) a group of the formula —NR³⁵R³⁶, wherein R³⁵ and R³⁶ are each,independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of1 to 2 carbon atoms;

R³ is a group of the formula —(CR³⁷R³⁸)_(x)(CR³⁹R⁴⁰)_(y)R⁴¹, wherein;

 x and y are each independently 0 or 1,

 R³⁷, R³⁸ and R³⁹ are each, independently:

(A) a hydrogen atom,

(B) a group of the formula —OR⁴², wherein R⁴² is a hydrogen atom, or analkyl or acyl group of 1 to 7 carbon atoms, or

(C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of3 to 5 carbon atoms,

 R⁴⁰ is:

(A) a hydrogen atom,

(B) a group of the formula —OR⁴², wherein R⁴² is a hydrogen atom, or analkyl or acyl group of 1 to 7 carbon atoms,

(C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of3 to 5 carbon atoms, or

(D) aryl which is selected from the class consisting of phenyl,2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl,2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl,3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl,2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3,6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-,3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-,3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl,2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or7-pteridinyl and 2-, 6- or 7-quinazolinyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) R⁴³, which is aryl selected from the class consisting of phenyl,2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl,2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl,3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl,2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3,6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-,3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-,3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl,2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or7-pteridinyl and 2-, 6- or 7-quinazolinyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(a) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(b) —COOH,

(c) —SO₂OH,

(d) —PO(OH)₂,

(e) a group of the formula —COOR⁴⁴, wherein R⁴⁴ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(f) a group of the formula —NR⁴⁵R⁴⁶, wherein R⁴⁵ and R⁴⁶ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or

 wherein R⁴⁵ and R⁴⁶ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

(g) a group of the formula —CONR⁴⁷R⁴⁸, wherein R⁴⁷ and R⁴⁸ are eachindependently a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁴⁷ and R⁴⁸constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,

(h) a group of the formula —OR⁴⁹, wherein R⁴⁹is a hydrogen atom, or analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

(i) a group of the formula —SR⁵⁰, wherein R⁵⁰ is a hydrogen atom, or analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

(j) cyano,

(k) nitro,

(l) an amidino group of the formula

 wherein R⁵¹, R⁵² and R⁵³ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and

 wherein two of R⁵¹, R⁵² and R⁵³ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, or

(m) halogen,

(ii) methyl, which may be mono- or polysubstituted with fluorine atomsand additionally may be monosubstituted with R⁴³,

(iii) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkylof 3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(iv) a group of the formula —COOR⁵⁴, wherein R⁵⁴ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(v) a group of the formula —NR⁵⁵R⁵⁶, wherein R⁵⁵ and R⁵⁶ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or wherein R⁵⁵ and R⁵⁶ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one of R⁵⁵ and R⁵⁶ may additionally bethe group R⁴³,

(vi) a group of the formula —CONR⁵⁷R⁵⁸, wherein R⁵⁷ and R⁵⁸ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁵⁷ and R⁵⁸constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one of R⁵⁷ and R⁵⁸ may additionally be the group R⁴³,

(vii) a group of the formula —COR⁵⁹, wherein R⁵⁹ is a hydrogen atom,straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5carbon atoms or R⁴³,

(viii) a group of the formula —OR⁶⁰, wherein R⁶⁰ is a hydrogen atom, analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁴³,

(ix) a group of the formula —SR⁶¹, wherein R⁶¹ is a hydrogen atom, analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁴³,

(x) cyano,

(xi) nitro, or

(xii) halogen,

 R⁴¹ is:

 aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-,5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4-or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl,2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5-or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl,3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyland 2-, 6- or 7-quinazolinyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl,2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl,2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl,3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl,2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3,6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-,3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-,3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl,2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or7-pteridinyl and 2-, 6- or 7-quinazolinyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(ii) —COOH,

(iii) —SO₂OH,

(iv) —PO(OH)₂,

(v) a group of the formula —COOR⁶³, wherein R⁶³ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(vi) a group of the formula —NR⁶⁴R⁶⁵, wherein R⁶⁴ and R⁶⁵ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or

 wherein R⁶⁴ and R⁶⁵ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

(vii) a group of the formula —CONR⁶⁶R⁶⁷, wherein R⁶⁶ and R⁶⁷ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁶⁶ and R⁶⁷constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,

(viii) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom, oran alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

(ix) a group of the formula —SR⁶⁹, wherein R⁶⁹ is a hydrogen atom, or analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

(x) cyano,

(xi) nitro, or

(xii) an amidino group of the formula

 wherein R⁷⁰, R⁷¹ and R⁷² are each, independently, a hydrogen atom oralkyl or fluoroalkyl of 1 to 3 carbon atoms, and wherein two of R⁷⁰, R⁷¹and R⁷² may additionally constitute a saturated hydrocarbon bridge of 3to 5 carbon atoms which together with the nitrogen atom(s) between themform a heterocyclic ring, or

(xiii) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atomsand additionally may be monosubstituted with R⁶²,

(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(D) a group of the formula —COOR⁷³, wherein R⁷³ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(E) a group of the formula —NR⁷⁴R⁷⁵, wherein R⁷⁴ and R⁷⁵ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or wherein R⁷⁴ and R⁷⁵ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one of R⁷⁴ and R⁷⁵ may additionally bethe group R⁶²,

(F) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ and R⁷⁷ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁷⁶ and R⁷⁷constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one of R⁷⁶ and R⁷⁷ may additionally be the group R⁶²,

(G) a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom,straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5carbon atoms or R⁶²,

(H) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁶²,

(I) a group of the formula —SR⁸⁰, wherein R⁸⁰ is a hydrogen atom, analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁶²,

(J) cyano,

(K) nitro, or

(L) halogen;

R⁴ is Cl or trifluoromethyl;

R⁵ is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl ortrifluoromethyl; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof.

Preferred are compounds of the formula I

wherein:

Y is an oxygen or sulfur atom;

Z is an oxygen or sulfur atom;

X is a divalent group of the formula >CHR¹, >NR¹, >CHSO₂R¹, or >NSO₂R¹,or an oxygen or sulfur atom,

 wherein R¹ is:

(A) a hydrogen atom,

(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may bemonosubstituted with:

(i) halogen,

(ii) oxo,

(iii) aryl selected from the class consisting of phenyl, naphthyl,indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl,thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,

 wherein one or more hydrogen atoms of said aryl group may be optionallyand independently replaced with:

(a) alkyl of 1 to 3 carbon atoms,

(b) —COOH,

(c) —SO₂OH,

(d) —PO(OH)₂,

(e) a group of the formula —COOR⁷, wherein R⁷ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(f) a group of the formula —NR⁸R⁹, wherein R⁸ and R⁹ are each,independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkylof 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R⁸ andR⁹ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring,

(g) a group of the formula —CONR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each,independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or

 wherein R¹⁰ and R ¹¹ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

(h) a group of the formula —OR^(12a), wherein R^(12a) is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

(i) a group of the formula —SR^(12b), wherein R^(12b) is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms,

(j) cyano, or

(k) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹³, R¹⁴ and R¹⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring,

(iv) a group of the formula —COOR¹⁶, wherein R¹⁶ is straight or branchedalkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,

(v) cyano,

(vi) a group of the formula —CONR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are each,independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms orcycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁷ and R¹⁸ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring,

(vii) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, oran alkyl or acyl group of 1 to 7 carbon atoms,

(viii) a group of the formula —SR²⁰, wherein R²⁰ is a hydrogen atom, oran alkyl or acyl group of 1 to 7 carbon atoms,

(ix) a group of the formula —NR²¹R²², wherein R²¹ and R²² are each,independently:

(a) a hydrogen atom,

(b) alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbonatoms,

(c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or 2, or

(d) a group of the formula —(CH₂)_(n)COOR²³, wherein n is 0, 1 or 2,wherein R²³ is straight or branched alkyl of 1 to 6 carbon atoms,

 or wherein R²¹ and R²² constitute a saturated hydrocarbon bridge of 3to 5 carbon atoms which together with the nitrogen atom between themform a heterocyclic ring, or

(x) a quatemary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is a chlorine,bromine or iodine counterion,

(C) a branched or unbranched carboxylic acid group of 3 to 6 carbonatoms,

(D) a branched or unbranched phosphonic acid group of 2 to 6 carbonatoms,

(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,

(F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and

 R²⁷, R²⁸ and R²⁹ are each, independently, a hydrogen atom or alkyl of 1to 3 carbon atoms and wherein two of R²⁷, R²⁸ and R²⁹ may additionallyconstitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom(s) between them form a heterocyclicring,

(G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6, and

 R³⁰, R³¹, R³² and R³³ are each independently a hydrogen atom or alkylof 1 to 3 carbon atoms and wherein two of R³⁰, R³¹, R³² and R³³ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, or

(H) piperidyl, wherein the nitrogen atom of said group is optionallysubstituted with:

(i) alkyl of 1 to 3 carbon atoms,

(ii) a carboxylic ester group of 2 to 7 carbon atoms,

(iii) a carboxylic acid group of 2 to 5 carbon atoms,

(iv) a phosphonic acid group of 1 to 6 carbon atoms, or

(v) a sulfonic acid group of 1 to 6 carbon atoms;

R² is:

(A) a hydrogen atom, or

(B) methyl;

R³ is a group of the formula —CH₂R⁴¹, wherein:

 R⁴¹ is:

 aryl selected from the class consisting of phenyl, 2-naphthyl, 2-, 3-,5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4-or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl,2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5-or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl,3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyland 2-, 6- or 7-quinazolinyl,

 wherein one or more of the hydrogen atoms of said aryl group arenecessarily and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl,2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl,2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl,3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl,2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3,6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-,3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-,3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl,2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or7-pteridinyl and 2-, 6- or 7-quinazolinyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(ii) —COOH,

(iii) —SO₂OH,

(iv) —PO(OH)₂,

(v) a group of the formula —COOR⁶³, wherein R⁶³ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(vi) a group of the formula —NR⁶⁴R⁶⁵, wherein R⁶⁴ and R⁶⁵ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or

 wherein R⁶⁴ and R⁶⁵ constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring,

(vii) a group of the formula —CONR⁶⁶R⁶⁷, wherein R⁶⁶ and R⁶⁷ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁶⁶ and R⁶⁷constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,

(viii) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom, oran alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

(ix) a group of the formula —SR⁶⁹, wherein R⁶⁹ is a hydrogen atom, or analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,

(x) cyano,

(xi) nitro,

(xii) an amidino group of the formula

 wherein R⁷⁰, R⁷¹ and R⁷² are each, independently, a hydrogen atom oralkyl or fluoroalkyl of 1 to 3 carbon atoms, and wherein two of R⁷⁰, R⁷¹and R⁷² may additionally constitute a saturated hydrocarbon bridge of 3to 5 carbon atoms which together with the nitrogen atom(s) between themform a heterocyclic ring, or

(xiii) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atomsand additionally may be monosubstituted with R⁶²,

(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(D) a group of the formula —COOR⁷³, wherein R⁷³ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(E) a group of the formula —NR⁷⁴R⁷⁵, wherein R⁷⁴ and R⁷⁵ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or wherein R⁷⁴ and R⁷⁵ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one of R⁷⁴ and R⁷⁵ may additionally bethe group R⁶²,

(F) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ and R⁷⁷ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁷⁶ and R⁷⁷constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms whichtogether with the nitrogen atom between them form a heterocyclic ring,and wherein one of R⁷⁶ and R⁷⁷ may additionally be the group R⁶²,

(G) a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom,straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5carbon atoms or R⁶²,

(H) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁶²,

(I) a group of the formula —SR⁸⁰, wherein R⁸⁰ is a hydrogen atom, analkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R⁶²,

(J) cyano,

(K) nitro, or

(L) halogen;

R⁴ is Cl or trifluoromethyl;

R⁵ is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl ortrifluoromethyl; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof.

More preferred are compounds of the formula I

wherein:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR¹ or >NR¹,

 wherein R¹ is:

(A) a hydrogen atom,

(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may bemonosubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

 wherein one or more hydrogen atoms of said aryl group may be optionallyand independently replaced with:

(a) alkyl of 1 to 3 carbon atoms,

(b) —COOH,

(c) —SO₂OH,

(d) —PO(OH)₂,

(e) a group of the formula —COOR⁷, wherein R⁷ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(f) a group of the formula —NH₂,

(g) a group of the formula —CONH₂,

(h) a group of the formula —OR^(12a), wherein R^(12a) is a hydrogen atomor a methyl,

(i) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms, a group of theformula —COOR¹ ⁶, wherein R¹⁶ is straight or branched alkyl of 1 to 7carbon atoms or cycloalkyl of 3 to 6 carbon atoms,

(k) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, or analkyl or acyl group of 1 to 7 carbon atoms, or

(l) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each methyl and Q⁻ is a chlorine, bromineor iodine counterion,

(C) a branched or unbranched carboxylic acid group of 3 to 6 carbonatoms,

(D) a branched or unbranched phosphonic acid group of 2 to 6 carbonatoms,

(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,

(F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and

 R²⁷, R²⁸ and R²⁹ are each hydrogen atoms,

(G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,

R³⁰, R³¹, R³² and R³³ are each hydrogen atoms, or

(H) piperidyl, wherein the nitrogen atom of said group is optionallysubstituted with:

(i) alkyl of 1 to 3 carbon atoms,

(ii) a carboxylic ester group of 2 to 7 carbon atoms,

(iii) a carboxylic acid group of 2 to 5 carbon atoms,

(iv) a phosphonic acid group of 1 to 6 carbon atoms, or

(v) a sulfonic acid group of 1 to 6 carbon atoms;

R² is:

(A) a hydrogen atom, or

(B) methyl;

R³ is a group of the formula —CH₂R⁴¹, wherein

 R⁴¹ is

 aryl selected from the class consisting of phenyl, thiophenyl, pyridyl,pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

 wherein one or more of the hydrogen atoms of said aryl group arenecessarily and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl,thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl,pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) methyl,

(ii) —COOH,

(iii) —SO₂OH,

(iv) —PO(OH)₂,

(v) a group of the formula —COOR⁶³, wherein R⁶³ is methyl,

(vi) a group of the formula —NR⁶⁴R⁶⁵, wherein R⁶⁴ and R⁶⁵ are each,independently, a hydrogen atom or methyl,

(vii) a group of the formula —CONR⁶⁶R⁶⁷, wherein R⁶⁶ and R⁶⁷ are each,independently, a hydrogen atom or methyl,

(viii) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom ormethyl,

(ix) a group of the formula —SR⁶⁹, wherein R⁶⁹ is a hydrogen atom ormethyl,

(x) cyano,

(xi) nitro, or

(xii) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atomsand which additionally may be monosubstituted with R⁶²,

(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(D) a group of the formula —COOR⁷³, wherein R⁷³ is methyl,

(E) a group of the formula —NR⁷⁴R⁷⁵, wherein R⁷⁴ and R⁷⁵ are each,independently, a hydrogen atom or methyl, and

 wherein one of R⁷⁴ and R⁷⁵ may additionally be the group R⁶²,

(F) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ and R⁷⁷ are each,independently, a hydrogen atom or methyl, and

 wherein one of R⁷⁶ and R⁷⁷ may additionally be the group R⁶²,

(G) a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom,methyl or R⁶²,

(H) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methylor R⁶²,

(I) a group of the formula —SR⁸⁰, wherein R⁸⁰ is a hydrogen atom, methylor R⁶²,

(J) cyano,

(K) nitro, or

(L) halogen;

R⁴ is Cl or trifluoromethyl;

R⁵ is a hydrogen atom; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof.

Even more preferred are compounds of the formula I:

wherein:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR¹ or >NR¹,

 wherein R¹ is:

(A) a hydrogen atom,

(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may bemonosubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl, thiophenyl,pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,

 wherein one or more hydrogen atoms of said aryl group may be optionallyand independently replaced with:

(a) alkyl of 1 to 3 carbon atoms,

(b) —COOH,

(c) —SO₂OH,

(d) —PO(OH)₂,

(e) a group of the formula —COOR⁷, wherein R⁷ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,

(f) a group of the formula —NH₂,

(g) a group of the formula —CONH₂,

(h) a group of the formula —OR^(12a), wherein R^(12a) is a hydrogen atomor a methyl,

(i) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms,

(j) a group of the formula —COOR¹⁶, wherein R¹⁶ is straight or branchedalkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,

(k) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, or analkyl or acyl group of 1 to 7 carbon atoms, or

(l) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each methyl and Q⁻ is a chlorine, bromineor iodine counterion,

(C) a branched or unbranched carboxylic acid group of 3 to 6 carbonatoms,

(D) a branched or unbranched phosphonic acid group of 2 to 6 carbonatoms,

(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,

(F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and

 R²⁷, R²⁸ and R²⁹ are each hydrogen atoms,

(G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,

 R³⁰, R³¹, R³² and R³³ are each hydrogen atoms, or

(H) piperidyl, wherein the nitrogen atom of said group is optionallysubstituted with:

(i) alkyl of 1 to 3 carbon atoms,

(ii) a carboxylic ester group of 2 to 7 carbon atoms,

(iii) a carboxylic acid group of 2 to 5 carbon atoms,

(iv) a phosphonic acid group of 1 to 6 carbon atoms, or

(v) a sulfonic acid group of 1 to 6 carbon atoms;

R² is:

(A) a hydrogen atom, or

(B) methyl;

R³ is a group of the formula —CH₂R⁴¹, wherein

 R⁴¹ is

 aryl selected from the class consisting of phenyl, thiophenyl, pyridyl,pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridazinyl, and pyrazinyl,

 wherein one or more of the hydrogen atoms of said aryl group arenecessarily and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl,thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, andpyrazinyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) methyl,

(ii) —COOH,

(iii) a group of the formula —COOR⁶³, wherein R⁶³ is methyl,

(iv) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom ormethyl, or

(v) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atoms orwhich may be monosubstituted with R⁶²,

(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo,

(D) a group of the formula —COOR⁷³, wherein R⁷³ is methyl,

(E) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ and R⁷⁷ are eachmethyl, and wherein one of R⁷⁶ and R⁷⁷ is methyl and the other is thegroup R⁶²,

(F) a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom,methyl or R⁶²,

(G) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methylor R⁶²,

(H) cyano,

(I) nitro, or

(J) halogen;

R⁴ is Cl or trifluoromethyl;

R⁵ is a hydrogen atom; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof.

Still more preferred are compounds of the formula I

wherein:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR¹ or >NR¹,

 wherein R¹ is:

(A) a hydrogen atom,

(B) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may bemonosubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl or pyridyl,

 wherein one or more hydrogen atoms of said aryl group may be optionallyand independently replaced with:

(a) alkyl of 1 to 3 carbon atoms,

(b) —COOH,

(c) —SO₂OH,

(d) —PO(OH)₂,

(e) a group of the formula —OR^(12a), wherein R^(12a) is a hydrogen atomor a methyl,

(f) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms,

(iii) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, oran alkyl or acyl group of 1 to 7 carbon atoms, or

(iv) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each methyl and Q⁻ is a chlorine, bromineor iodine counterion,

(C) a branched or unbranched carboxylic acid group of 3 to 6 carbonatoms,

(D) a branched or unbranched phosphonic acid group of 2 to 6 carbonatoms,

(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,

(F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and

 R²⁷, R²⁸ and R²⁹ are each hydrogen atoms,

(G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,

 R³⁰, R³¹, R³² and R³³ are each hydrogen atoms, or

(H) piperidyl, wherein the nitrogen atom of said group is optionallysubstituted with:

(i) alkyl of 1 to 3 carbon atoms,

(ii) a carboxylic ester group of 2 to 7 carbon atoms,

(iii) a carboxylic acid group of 2 to 5 carbon atoms,

(iv) a phosphonic acid group of 1 to 6 carbon atoms, or

(v) a sulfonic acid group of 1 to 6 carbon atoms;

R² is:

(A) a hydrogen atom, or

(B) methyl;

R³ is a group of the formula —CH₂R⁴¹, wherein

 R⁴¹ is

 aryl selected from the class consisting of phenyl or pyridyl,

 wherein one or more of the hydrogen atoms of said aryl group arenecessarily and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl, orpyridyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) methyl,

(ii) —COOH

(iii) a group of the formula —COOR⁶³, wherein R⁶³ is methyl,

(iv) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom ormethyl, or

(v) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atoms orwhich may be monosubstituted with R⁶²,

(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with fluorine or oxo,

(D) a group of the formula —COOR⁷³, wherein R⁷³ is methyl,

(E) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ and R⁷⁷ are eachmethyl, and wherein one of R⁷⁶ and R⁷⁷ is methyl and the other is thegroup R⁶²,

(F) a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom,methyl or R⁶²,

(G) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methylor R⁶²,

(H) cyano,

(I) nitro, or

(J) halogen;

R⁴ is Cl or trifluoromethyl;

R⁵ is a hydrogen atom; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof

Especially preferred are compounds of the formula I

wherein:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >CHR¹ or >NR¹,

 R¹ is:

(A) a hydrogen atom,

(B) alkyl of 1 to 2 carbon atoms which may be monosubstituted with:

(i) oxo,

(ii) aryl selected from the class consisting of phenyl or pyridyl,

 wherein one hydrogen atom of said aryl group may be optionally replacedwith:

(a) alkyl of 1 to 3 carbon atoms,

(b) —COOH,

(c) —SO₂OH,

(d) —PO(OH)₂,

(e) a group of the formula —OR^(12a), wherein R^(12a) is a hydrogen atomor a methyl, or

(f) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms, or

(iii) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogen atom ormethyl,

(C) a branched or unbranched carboxylic acid group of 3 to 6 carbonatoms,

(D) a branched or unbranched phosphonic acid group of 2 to 6 carbonatoms,

(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,

(F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and

 R²⁷, R²⁸ and R²⁹ are each hydrogen atoms, or

(G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,

 R³⁰, R³¹, R³² and R³³ are each hydrogen atoms,

R² is:

(A) a hydrogen atom, or

(B) methyl;

R³ is a group of the formula —CH₂R⁴¹, wherein

 R⁴¹ is

 phenyl

 wherein one or more of the hydrogen atoms of said phenyl group arenecessarily and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl, orpyridyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) methyl,

(ii) a group of the formula —COOR⁶³, wherein R⁶³ is methyl,

(iii) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom ormethyl, or

(iv) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atoms orwhich may be monosubstituted with R⁶²,

(C) a group of the formula —COOR⁷³, wherein R⁷³ is methyl,

(D) a group of the formula —COR⁷⁸, wherein R⁷⁸ is methyl or R⁶²,

(E) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methylor R⁶²,

(F) cyano,

(G) nitro, or

(H) halogen;

R⁴ is Cl or trifluoromethyl;

R⁵ is a hydrogen atom; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof.

Even more especially preferred are compounds of the formula I

wherein:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >NR¹,

 R¹ is:

(A) a hydrogen atom,

(B) methyl or ethyl, or

(C) —COCH₃

R² is:

(A) a hydrogen atom, or

(B) methyl;

R³ is a group of the formula —CH₂R⁴¹, wherein

 R⁴¹ is

 phenyl

 wherein one or more of the hydrogen atoms of said phenyl group arenecessarily and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl, orpyridyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) methyl,

(ii) a group of the formula —COOR⁶³, wherein R⁶³ is methyl,

(iii) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom ormethyl, or

(iv) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atoms orwhich may be monosubstituted with R⁶²,

(C) a group of the formula —COOR⁷³, wherein R⁷³ is methyl,

(D) a group of the formula —COR⁷⁸, wherein R⁷⁸ is methyl or R⁶²,

(E) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methylor R⁶²,

(F) cyano,

(G) nitro, or

(H) halogen;

R⁴ is Cl or trifluoromethyl;

R⁵ is a hydrogen atom; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof.

Penultimately preferred are compounds of the formula I

wherein:

Y is an oxygen atom;

Z is an oxygen atom;

X is a divalent group of the formula >NR¹,

 R¹ is:

(A) a hydrogen atom,

(B) methyl or ethyl, or

(C) —COCH₃

 R² is:

(A) a hydrogen atom, or

(B) methyl;

R³ is a group of the formula —CH₂R⁴¹, wherein

 R⁴¹ is

 phenyl

 wherein one or more of the hydrogen atoms of said phenyl group arenecessarily and independently replaced with:

(A) R⁶², which is aryl selected from the class consisting of phenyl, orpyridyl,

 wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with:

(i) methyl, or

(ii) halogen,

(B) methyl, which may be mono- or polysubstituted with fluorine atoms,

(C) a group of the formula —COR⁷⁸, wherein R⁷⁸ is methyl or R⁶²,

(D) halogen;

R⁴ is a chlorine atom;

R⁵ is a hydrogen atom; and,

R⁶ is CN or NO₂;

and pharmaceutically acceptable salts thereof.

Ultimately preferred are the following compounds of the formula I:

5-(R)-(4-bromobenzyl)-3-(3-chloro-5-nitrophenyl)-5-methylimidazoline-2,4-dione; and,

5-(R)-(4-bromobenzyl)-3 -(3 -chloro-5-cyanophenyl)-5-methylimidazoline-2,4-dione;

and pharmaceutically acceptable salts thereof.

It will be appreciated that the compounds of the formula I have at leastone chiral center. Most preferred are those compounds of formula I withthe absolute stereochemistry depicted below in formula Ia.

Synthesis of the Compounds of the Invention

Compounds of the invention may be prepared by the general methodsdescribed below. Typically, reaction progress may be monitored by thinlayer chromatography (TLC) if desired. If desired, intermediates andproducts may be purified by chromatography on silica gel and/orrecrystallization. Starting materials and reagents are eithercommercially available or may be prepared by one skilled in the artusing methods described in the chemical literature.

Intermediates used in the preparation of the compounds of formula I maybe prepared by the method described below and outlined in Scheme I.

The isocyanate derivative of the appropriate amino acid (III) is reactedwith the desired aniline (IV) in a suitable solvent such as THF plusHMPA, in the presence of a suitable base, such as potassiumbis(trimethylsilyl)amide Following workup, consisting of washing withaqueous acid, such as aqueous ammonium chloride followed bypurification, for example by silica gel chromatography orrecrystallization, the desired Ib is obtained.

If the thiocarbonyl is desired, several reagents are known in theliterature which will convert carbonyls to thio carbonyls. A typicalsequence involves heating the substrate with a reagent such as P₂S₃ in ahigh boiling solvent such as tetralin for between 1 and 48 hr. Isolationof the product follows relatively standard conditions such as thedilution of the mixture into an organic solvent such as EtOAc andwashing this mixture with water and saturated aqueous NaCl followed bydrying and concentration. Purification is accomplished by silica gelchromatography or recrystallization, to afford Ic.

This compound can be selectively hydrolyzed to the desiredmonothiocarbonyl compound depending on the choice of conditions. Ingeneral the thiocarbonyl at the 4-position of the ring is moresusceptible to nucleophilic conditions. It can be converted to the4-oxo-species (Id) by treatment with aqueous ethanolamine followed byacid hydrolysis Purification is easily performed by silica gelchromatography or recrystallization.

Alternatively, the isothiocyanate derivative of the methyl or ethylester of III may be reacted with IV in a suitable solvent, such as1,4-dioxane, under an inert atmosphere at about 50-100° C. for about1-24 hr to provide Id. If one uses the racemic III or ester of III, theproduct is racemic at the asymmetric carbon. By starting with a singleenantiomer of III or ester of III, one obtains the single enantiomer ofId.

The starting amino acids and their derivatives necessary for thesynthesis of the hydantoin and thio-hydantoin structures are eithercommercially available or are produced by obvious modifications of knownliterature procedures (see e.g.: Williams, R. W. Synthesis of OpticallyActiveα-Amino Acids; Pergamon: Oxford, 1989, α-Amino Acid Synthesis;O'Donnell, M. J., Ed.; Tetrahedron Symposium in Print; Pergamon: London,1988: Vol. 44, Issue 17, Jung, M. J. Chemistry and Biochemistry of theAmino Acids; Barrett, G. C., Ed.; Chapman and Hall: New York, 1985;p.227, and Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1996, 61:7398-7401). The synthesis and resolution of ethyl2-amino-2-(4-bromobenzyl)-propanoate is given by way of example.

A solution of alanine ethyl ester hydrochloride (15.3 g, 99.3 mmol) in60 mL of water was treated with triethylamine (14.6 mL, 104.8 mmol) atroom temperature for 30 min. The mixture was then extracted twice with100 mL of methylene chloride. The organic layers were combined, driedover sodium sulfate, and concentrated in vacuo to afford 10.0 g of thefree base of the amino ester (86% yield). The residue was re-dissolvedin methylene chloride and cooled in an ice bath. Magnesium sulfate (11.3g, 93.9 mmol) was added, followed by trimethyl acetaldehyde (9.3 mL,85.6 mmol). The ice bath was removed, and the mixture was stirredovernight. The magnesium sulfate was removed by filtration, and thefiltrate was concentrated in vacuo to afford 11.8 g of the imineintermediate (74.6% yield).

The imine from above (11.8 g, 63.7 mmol) was dissolved in toluene (90mL). 4-bromobenzyl bromide (17.5 g, 70.1 mmol) was added, and thereaction was cooled to about −10° C. Potassium tert-butoxide (8.6 g,76.5 mmol) was added at such a rate that the temperature did not exceed0° C. The reaction stirred in the cold bath for two hours, then wasdiluted with ether and washed with water (150 mL). The organic layer wasdried (sodium sulfate), filtered, and concentrated in vacuo to afford aclear yellow oil. This was treated with 1 N HCl (100 ml, 100 mmol) andstirred overnight. The reaction was extracted with ethyl acetate (100mL), and the aqueous layer was to afford 14.1 g of the racemic aminoester hydrochloride (68.7% yield). Isocyanate derivatives can be made byreacting the aminoacid ester with a phosgene equivalent such astrichloromethyl chloroformate. This is exemplified in the SyntheticExamples below.

The racemic compounds can be resolved into their component enantiomersvia a number of known techniques. Ethyl2-(R)-amino-2-(4-bromobenzyl)-propanoate was produced from racemic ethyl2-amino-2-(4-bromobenzyl)-propanoate by the following procedure: To 1.3L of a buffer made from 13.69 g KH₂PO₄ and 2 L of water was added 20 gof the commercially available enzyme Lipase L10 (Amano Enzyme USA Co.,Ltd, Lombardi, Ill.) followed by 12 g of the HCl salt of the racemicamino ester. The pH was monitored and 1 N KOH was added as needed tokeep the pH of the mixture at 6.4. The course of the reaction wasmonitored with reverse phase HPLC and after 2 days, the HPLC analysisindicated that 50.4% of the starting material had been hydrolyzed. Atthis point enough solid NaHCO₃ was added to adjust the pH to 8.1 and themixture was extracted twice with toluene, ether and EtOAc. The combinedorganic layers was dried and concentrated and the crude product purifiedby silica gel chromatography (EtOAC: Hexanes) to yield 5.21 g (87%) ofethyl 2-(R)-amino-2-(4-bromobenzyl)-propanoate. Modifications to theabove procedures and further transformations of initial products toobtain additional compounds of the invention are known to those skilledin the art and are analogous to those described in WO 9839303.

SYNTHETIC EXAMPLES Example 1 Synthesis of5-(R)-(4-bromobenzyl)-3-(3-chloro-5-nitrophenyl)-5-methylimidazoline-2,4-dione

A solution of 0.40 g (5.73 mmol) sodium nitrite in 1 mL H₂O was addeddropwise to a stirred suspension of 1.00 g (5.46 mmol)3,5-dinitroaniline in 5 mL H₂O and 2.5 mL conc. HCl in an ice bath.After 5 min, a solution of 0.70 g (7.10 mmol) copper (I) chloride in 2mL conc. HCl was added dropwise. About 5 mL of toluene was added and thereaction was allowed to warm to room temperature and then heated 1 hr at60° C. The reaction was diluted with water, extracted (4×EtOAc), washedwith H₂O and aqueous Na₂CO₃, dried and concentrated in vacuo to give 1.3g of a dark oil. Silica gel flash chromatography, eluting with 5%EtOAc-pet ether afforded 1-chloro-3,5-dinitrobenzene (0.86 g, 78%) as ayellow oil.

The above product (0.50 g, 2.47 mmol) was refluxed 1 hr in 6 mL alcoholand 3 mL 20% ammonium sulfide in H₂O. Water was added and the productwas filtered, dried and flash chromatographed on silica gel eluting with10% acetone-pet ether to obtain 3-chloro-5-nitroaniline (0.36 g, 84%) asan orange powder.

Trichloromethylchloroformate (0.233 mL, 1.93 mmol) was added to a twophase mixture of 50 mL aqueous NaHCO₃ and 1.00 g (3.68 mmol) of(R)-α-methyl-4-bromophenylalanine methyl ester in 50 mL CH₂Cl₂ at 0° C.After stirring 10 min in the cold, the phases were separated and theaqueous phase was extracted 3× more with CH₂Cl₂. The combined organicphase was dried, concentrated in vacuo to a semisolid, re-dissolved inCH₂Cl₂, filtered through silica gel, and concentrated again to 0.62 g(56%) oil as the pure isocyanate.

A solution of 1.1 mL (0.55 mmol) of 0.5 M potassiumbis(trimethylsilyl)amide in toluene was added to a solution of 0.095 g(0.55 mmol) 3-chloro-5-nitroaniline in 5 mL dry THF and 0.25 mL HMPA ina flame-dried flask under argon in a dry ice-alcohol bath. Afterstirring 5 min, a solution of the isocyanate (0.164 g, 0.55 mmol) in 1.5mL THF was added dropwise over 10 min and stirred for another 0.5 hr inthe cold. Aqueous NH₄Cl was added which was then extracted 4× withether, dried and concentrated in vacuo to an oil. The crude product waspurified on Analtech 2 mm prep plates, developed in 20% acetone-petether, and isolated and developed again on another plate in 5% EtOAc-CH₂Cl₂ to afford 60.6 mg (25%) of the title compound as a sticky resin.

Example 2 Synthesis of5-(R)-(4-bromobenzyl)-3-(3-chloro-5-cyanophenyl)-5-methylimidazoline-2,4-dione.

5-(R)-(4-bromobenzyl)-3-(5-acetamino-3-chlorophenyl)-5-methylimidazoline-2,4-dione(prepared by the process described in Example 1 from the isocyanatederivative of (R)-α-methyl-4-bromophenylalanine methyl ester and5-acetamino-3-chloroaniline) was hydrolyzed by heating in 2N HCl to give5-(R)-(4-bromobenzyl)-3-(5-amino-3-chlorophenyl)-5-methylimidazoline-2,4-dione.Sandmeyer reaction with NaNO₂, CuCN and KCN provided the title compoundas a resin.

Description of Biological Properties

The biological properties of representative compounds of the formula Iwere investigated by way of the experimental protocol described below.

Assay to Determine Inhibition of LFA-1 Binding to ICAM-1

Purpose of Assay:

This assay protocol is designed to study the direct antagonism, by atest compound, of the interaction of the CAM, ICAM-1 with theLeukointegrin CD18/CD11a (LFA-1).

Description of Assay Protocol:

LFA-1 is immunopurified using the TS2/4 antibody from a 20 g pellet ofhuman JY or SKW3 cells, utilizing a protocol previously described(Dustin, M. J.; et al., J. Immunol. 1992, 148, 2654-2660). The LFA-1 ispurified from SKW3 lysates by immunoaffinity chromatography on TS2/4LFA-1 mAb Sepharose and eluted at pH 11.5 in the presence of 2 mM MgCl₂and 1% octylglucoside. After collection and neutralization of fractionsfrom the TS2/4 column, samples are pooled and precleared with Protein Gagarose.

A soluble form of ICAM-1 is constructed, expressed, purified andcharacterized as previously described (Marlin, S.; et al., Nature, 1990,344, 70-72 and see Arruda, A.; et al., Antimicrob. Agents Chemother.1992, 36, 1186-1192). Briefly, isoleucine 454 which is located at theputative boundary between domain 5 of the ectodomain and thetransmembrane domain, is changed to a stop codon using standardoligonucleotide-directed mutagenesis. This construction yields amolecule identical with the first 453 amino acids of membrane boundICAM-1. An expression vector is created with a hamster dihydrofolatereductase gene, a neomycin-resistance marker, and the coding region ofthe sICAM-1 construct described above, along with the promoter, splicesignals, and polyadenylation signal of the SV40 early region. Therecombinant plasmid is transfected into CHO DUX cells using standardcalcium phosphate methods. Cells are passaged in selective media (G418)and colonies secreting sICAM-1 are amplified using methotrexate. sICAM-1is purified from serum-free media using traditional non-affinitychromatographic techniques, including ion exchange and size exclusionchromatography.

LFA-1 binding to ICAM-1 is monitored by first incubating sICAM-1 at 40μg/mL in Dulbecco's phosphate buffered saline with calcium andmagnesium, additional 2 mM MgCl₂ and 0.1 mM PMSF (Diluting Buffer) in a96-well plate for 30 min at room temperature. Plates are then blocked bythe addition of 2% (w/v) bovine serum albumin in Diluting Buffer for 37°C. for 1 h. Blocking solution is removed from wells, and test compoundsare diluted and then added followed by the addition of approximately 25ng of immunoaffinity purified LFA-1. The LFA-1 is incubated in thepresence of test compound and ICAM-1 at 37° C. for 1 h. Wells are washed3 times with Diluting Buffer. The bound LFA-1 is detected by theaddition of a polyclonal antibody directed against a peptidecorresponding to the CD 18 cytoplasmic tail in a 1:100 dilution withDiluting Buffer and 1% BSA and allowed to incubate for 45 min at 37° C.Wells are washed 3 times with Diluting Buffer and the bound polyclonalantibody is detected by the addition of a 1:4000 dilution of horseradish peroxidase conjugated to goat immunoglobulin directed againstrabbit immunoglobulin. This reagent is allowed to incubate for 20 min at37° C., wells are washed as above and the substrate for the horse radishperoxidase is added to each well to develop a quantitative colorimetricsignal proportional to the amount of LFA-1 bound to sICAM-1. SolubleICAM-1 (60 μg/mL) is used as a positive control for inhibition of theLFA-1/ICAM-1 interaction. The lack of the addition of LFA-1 to thebinding assay is used as a background control for all samples. Adose-response curve is obtained for all test compounds.

All compounds made in the above examples were tested in this assay andeach found to have a K_(d)<10 μM.

Description of Therapeutic Use

The novel small molecules of formula I provided by the invention inhibitthe ICAM-1/LFA-1 dependent homotypic aggregation of human lymphocytesand human lymphocyte adherence to ICAM-1. These compounds havetherapeutic utility in the modulation of immune cellactivation/proliferation, e.g., as competitive inhibitors ofintercellular ligand/receptor binding reactions involving CAMs andLeukointegrins. To be more specific, the compounds of the invention maybe used to treat certain inflammatory conditions, including conditionsresulting from a response of the non-specific immune system in a mammal(e.g., adult respiratory distress syndrome, shock, oxygen toxicity,multiple organ injury syndrome secondary to septicemia, multiple organinjury syndrome secondary to trauma, reperfusion injury of tissue due tocardiopulmonary bypass, myocardial infarction or use with thrombolysisagents, acute glomerulonephritis, vasculitis, reactive arthritis,dermatosis with acute inflammatory components, stroke, thermal injury,hemodialysis, leukapheresis, ulcerative colitis, necrotizingenterocolitis and granulocyte transfusion associated syndrome) andconditions resulting from a response of the specific immune system in amammal (e.g., psoriasis, organ/tissue transplant rejection, graft vs.host reactions and autoimmune diseases including Raynaud's syndrome,autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoidarthritis, insulin-dependent diabetes mellitus, uveitis, inflammatorybowel disease including Crohn's disease and ulcerative colitis, andsystemic lupus erythematosus). The compounds of the invention may alsobe used in treating asthma or as an adjunct to minimize toxicity withcytokine therapy in the treatment of cancers. In general these compoundsmay be employed in the treatment of those diseases currently treatablethrough steroid therapy.

Thus, another aspect of the invention is the provision of a method forthe treatment or prophylaxis of the above-described conditions throughthe adminstration of therapeutic or prophylactic amounts of one or morecompounds of the formula I.

In accordance with the method provided by the invention, the novelcompounds of formula I may be administered for either a “prophylactic”or “therapeutic” purpose either alone or with other immunosuppressive orantiinflammatory agents. When provided prophylactically, theimmunosuppressive compound(s) are provided in advance of anyinflammatory response or symptom (for example, prior to, at, or shortlyafter the time of an organ or tissue transplant but in advance of anysymptoms of organ rejection). The prophylactic administration of acompound of the formula I serves to prevent or attenuate any subsequentinflammatory response (such as, for example, rejection of a transplantedorgan or tissue, etc.). The therapeutic administration of a compound ofthe formula I serves to attenuate any actual inflammation (such as, forexample, the rejection of a transplanted organ or tissue). Thus, inaccordance with the invention, a compound of the formula I can beadministered either prior to the onset of inflammation (so as tosuppress an anticipated inflammation) or after the initiation ofinflammation.

The novel compounds of the formula I may, in accordance with theinvention, be administered in single or divided doses by the oral,parenteral or topical routes. A suitable oral dosage for a compound offormula I would be in the range of about 0.1 mg to 10 g per day. Inparenteral formulations, a suitable dosage unit may contain from 0.1 to250 mg of said compounds, whereas for topical administration,formulations containing 0.01 to 1% active ingredient are preferred. Itshould be understood, however, that the dosage administration frompatient to patient will vary and the dosage for any particular patientwill depend upon the clinician's judgement, who will use as criteria forfixing a proper dosage the size and condition of the patient as well asthe patient's response to the drug.

When the compounds of the present invention are to be administered bythe oral route, they may be administered as medicaments in the form ofpharmaceutical preparations which contain them in association with acompatible pharmaceutical carrier material. Such carrier material can bean inert organic or inorganic carrier material suitable for oraladministration. Examples of such carrier materials are water, gelatin,talc, starch, magnesium stearate, gum arabic, vegetable oils,polyalkylene-glycols, petroleum jelly and the like.

The pharmaceutical preparations can be prepared in a conventional mannerand finished dosage forms can be solid dosage forms, for example,tablets, dragees, capsules, and the like, or liquid dosage forms, forexample solutions, suspensions, emulsions and the like.

The pharmaceutical preparations may be subjected to conventionalpharmaceutical operations such as sterilization. Further, thepharmaceutical preparations may contain conventional adjuvants such aspreservatives, stabilizers, emulsifiers, flavor-improvers, wettingagents, buffers, salts for varying the osmotic pressure and the like.Solid carrier material which can be used include, for example, starch,lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc,silica, dibasic calcium phosphate, and high molecular weight polymers(such as polyethylene glycol).

For parenteral use, a compound of formula I can be administered in anaqueous or non-aqueous solution, suspension or emulsion in apharmaceutically acceptable oil or a mixture of liquids, which maycontain bacteriostatic agents, antioxidants, preservatives, buffers orother solutes to render the solution isotonic with the blood, thickeningagents, suspending agents or other pharmaceutically acceptableadditives. Additives of this type include, for example, tartrate,citrate and acetate buffers, ethanol, propylene glycol, polyethyleneglycol, complex formers (such as EDTA), antioxidants (such as sodiumbisulfite, sodium metabisulfite, and ascorbic acid), high molecularweight polymers (such as liquid polyethylene oxides) for viscosityregulation and polyethylene derivatives of sorbitol anhydrides.Preservatives may also be added if necessary, such as benzoic acid,methyl or propyl paraben, benzalkonium chloride and other quaternaryammonium compounds.

The compounds of this invention may also be administered as solutionsfor nasal application and may contain in addition to the compounds ofthis invention suitable buffers, tonicity adjusters, microbialpreservatives, antioxidants and viscosity-increasing agents in anaqueous vehicle. Examples of agents used to increase viscosity arepolyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone,polysorbates or glycerin. Microbial preservatives added may includebenzalkonium chloride, thimerosal, chloro-butanol or phenylethylalcohol.

Additionally, the compounds provided by the invention can beadministered by suppository.

Formulations

Compounds of the formula I can be formulated for therapeuticadministration in a number of ways. Descriptions of several exemplaryformulations are given below.

Example A

Capsules or Tablets

Example A-1 Example A-2 Ingredients Quantity Ingredients QuantityCompound of 250 mg Compound of  50 mg formula I formula I Starch 160 mgDicalcium Phosphate 160 mg Microcrys. Cellulose  90 mg Microcrys.Cellulose  90 mg Sodium Starch  10 mg Stearic acid  5 mg GlycolateMagnesium Stearate  2 mg Sodium Starch  10 mg Glycolate Fumed colloidalsilica  1 mg Fumed colloidal silica  1 mg

The compound of formula I is blended into a powder mixture with thepremixed excipient materials as identified above with the exception ofthe lubricant. The lubricant is then blended in and the resulting blendcompressed into tablets or filled into hard gelatin capsules.

Example B

Parenteral Solutions

Ingredients Quantity Compound of formula I 500 mg PEG 400 40% by volumeEthyl Alcohol 5% by volume Saline 55% by volume

The excipient materials are mixed and then added to one of the compoundsof formula I in such volume as is necessary for dissolution. Mixing iscontinued until the solution is clear. The solution then filtered intothe appropriate vials or ampoules and sterilized by autoclaving.

Example C

Suspension

Ingredients Quantity Compound of formula I 100 mg Citric acid 1.92 gBenzalkonium chloride 0.025% by weight EDTA 0.1% by weightPolyvinylalcohol 10% by weight Water q.s. to 100 mL

The excipient materials are mixed with the water and thereafter one ofthe compounds of formula I is added and mixing is continued until thesuspension is homogeneous. The suspension is then transferred into theappropriate vials or ampoules.

What is claimed is:
 1. A compound of the formula I

wherein: Y is an oxygen or sulfur atom; Z is an oxygen or sulfur atom; Xis a divalent group of the formula >NR¹ or >NSO₂R¹,  wherein R¹ is: (A)a hydrogen atom, (B) branched or unbranched alkyl of 1 to 6 carbon atomsor cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group maybe mono- or polysubstituted with: (i) halogen, (ii) oxo, (iii) aryl,which is selected from the class consisting of phenyl, naphthyl,indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl,thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,  wherein one or more hydrogen atoms of saidaryl group may be optionally and independently replaced with: (a) alkylof 1 to 3 carbon atoms, (b) —COOH, (c) —SO₂OH, (d) —PO(OH)₂, (e) a groupof the formula —COOR⁷, wherein R⁷ is straight or branched alkyl of 1 to5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of theformula —NR⁸R⁹, wherein R⁸ and R⁹ are each independently a hydrogenatom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms oracyl of 1 to 7 carbon atoms, or wherein R⁸ and R⁹ constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom between them form a heterocyclic ring, (g) a group of theformula —CONR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each independently ahydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6carbon atoms, or wherein R¹⁰ and R¹¹ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, (h) a group of the formula—OR^(12a), wherein R^(12a) is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, (i) a group of the formula —SR^(12b), whereinR^(12b) is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbonatoms, (j) cyano, or (k) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹³, R¹⁴ and R¹⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (iv) a group of the formula —COOR¹⁶, wherein R¹⁶ isstraight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to6 carbon atoms, (v) cyano, (vi) a group of the formula —CONR¹⁷R¹⁸,wherein R¹⁷ and R¹⁸ are each, independently, a hydrogen atom, alkyl of 1to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁷and R¹⁸ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, (vii) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms, (viii) a groupof the formula —SR²⁰, wherein R²⁰ is a hydrogen atom, or an alkyl oracyl group of 1 to 7 carbon atoms, (ix) a group of the formula —NR²¹R²²,wherein R²¹ and R²² are each, independently, (a) a hydrogen atom, (b)alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbonatoms, (c) a group of the formula —CH₂)_(m)COOH , wherein m is 0, 1 or2, or (d) a group of the formula —CH₂)_(n)COOR²³, wherein n is 0, 1 or2, wherein R²³ is straight or branched alkyl of 1 to 6 carbon atoms,  orwherein R²¹ and R²² constitute a saturated hydrocarbon bridge of 3 to 5carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, or (x) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is a chlorine,bromine or iodine counterion, (C) a branched or unbranched carboxylicacid group of 3 to 6 carbon atoms, (D) a branched or unbranchedphosphonic acid group of 2 to 6 carbon atoms, (E) a branched orunbranched sulfonic acid group of 2 to 6 carbon atoms, (F) an amidinogroup of the formula

 wherein r is 2, 3, 4, 5 or 6, and  R²⁷, R²⁸ and R²⁹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R²⁷, R²⁸ and R²⁹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, (G) an guanidinogroup of the formula

 wherein s is 2, 3, 4, 5 or 6, and  R³⁰, R³¹, R³² and R³³ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, andwherein two of R³⁰, R³¹, R³² and R³³ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring, (H)piperidyl, wherein the nitrogen atom of said group is optionallysubstituted with: (i) alkyl of 1 to 3 carbon atoms, (ii) a carboxylicester group of 2 to 7 carbon atoms, (iii) a carboxylic acid group of 2to 5 carbon atoms, (iv) a phosphonic acid group of 1 to 6 carbon atoms,or (v) a sulfonic acid groups of 1 to 6 carbon atoms, or (I) aryl whichis selected from the class consisting of phenyl, naphthyl, indolyl,thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl,pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl,quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl,pteridinyl and quinazolinyl,  wherein one or more hydrogen atoms of saidaryl group may be optionally and independently replaced with: (i) alkylof 1 to 3 carbon atoms, (ii) —COOH, (iii) —SO₂OH, (iv) —PO(OH)₂, (v) agroup of the formula —COOR⁷, wherein R⁷ is straight or branched alkyl of1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a groupof the formula —NR⁸R⁹, wherein R⁸ and R⁹ are each, independently, ahydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbonatoms or acyl of 1 to 7 carbon atoms, or wherein R⁸ and R⁹ constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom between them form a heterocyclic ring, (vii) a groupof the formula —CONR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each, independently,a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6carbon atoms, or wherein R¹⁰ and R¹¹ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, (viii) a group of the formula—OR^(12a), wherein R^(12a) is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, (ix) a group of the formula —SR^(12b), whereinR^(12b) is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbonatoms, (x) cyano, or (xi) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and wherein two of R¹³, R¹⁴ and R¹⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring;  R² is: (A) a hydrogen atom, or (B) branched orunbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbonatoms wherein said alkyl or cycloalkyl group may optionally besubstituted with: (i) a group of the formula —OR³⁴, wherein R³⁴ is ahydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or (ii)a group of the formula —NR³⁵R³⁶, wherein R³⁵ and R³⁶ are each,independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of1 to 2 carbon atoms; R³ is a group of the formula—(CR³⁷R³⁸)_(x)(CR³⁹R⁴⁰)_(y)R⁴¹, wherein;  x and y are each independently0 or 1,  R³⁷, R³⁸ and R³⁹ are each, independently: (A) a hydrogen atom,(B) a group of the formula —OR⁴², wherein R⁴² is a hydrogen atom, or analkyl or acyl group of 1 to 7 carbon atoms, or (C) branched orunbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbonatoms,  R⁴⁰ is: (A) a hydrogen atom, (B) a group of the formula —OR⁴²,wherein R⁴² is a hydrogen atom, or an alkyl or acyl group of 1 to 7carbon atoms, (C) branched or unbranched alkyl of 1 to 3 carbon atoms orcycloalkyl of 3 to 5 carbon atoms, or (D) aryl which is selected fromthe class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2-or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-,4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-,4- or 5-triazolyl, 2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl,2-triazinyl, 2-, -3, 6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl,2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-,5- or 6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl,2- or 8-purinyl, 2-, 3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl,6- or 7-pthalaninyl, 2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or7-napthyridinyl, 2-, 6- or 7-pteridinyl and 2-, 6- or 7-quinazolinyl, wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with: (i) R⁴³, which is arylselected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4-or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl,2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5-or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl,3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyland 2-, 6- or 7-quinazolinyl,  wherein one or more of the hydrogen atomsof said aryl group may be optionally and independently replaced with:(a) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of3 to 6 carbon atoms, which alkyl or cycloakyl group may be mono- orpolysubstituted with halogen or oxo, (b) —COOH, (c) —SO₂OH, (d)—PO(OH)₂, (e) a group of the formula —COOR⁴⁴, wherein R⁴⁴ is straight orbranched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbonatoms, (f) a group of the formula —NR⁴⁵R⁴⁶, wherein R⁴⁵ and R⁴⁶ areeach, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbonatoms, or wherein R⁴⁵ and R⁴⁶ constitute a saturated hydrocarbon bridgeof 3 to 5 carbon atoms which together with the nitrogen atom betweenthem form a heterocyclic ring, (g) a group of the formula —CONR⁴⁷R⁴⁸,wherein R⁴⁷ and R⁴⁸ are each independently a hydrogen atom, alkyl orfluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,or wherein R⁴⁷ and R⁴⁸ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, (h) a group of the formula —OR⁴⁹, wherein R⁴⁹ is ahydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbonatoms, (i) a group of the formula —SR⁵⁰, wherein R⁵⁰ is a hydrogen atom,or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, (j)cyano, (k) nitro, (l) an amidino group of the formula

 wherein R⁵¹, R⁵² and R⁵³ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms, and wherein two of R⁵¹, R⁵² and R⁵³ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, or (m) halogen, (ii) methyl, which may be mono- orpolysubstituted with fluorine atoms and additionally may bemonosubstituted with R⁴³, (iii) branched or unbranched alkyl of 2 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl orcycloakyl group may be mono- or polysubstituted with halogen or oxo,(iv) a group of the formula —COOR⁵⁴, wherein R⁵⁴ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (v) agroup of the formula —NR⁵⁵R⁵⁶, wherein R⁵⁵ and R⁵⁶ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or wherein R⁵⁵ and R⁵⁶ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one of R⁵⁵ and R⁵⁶ may additionally bethe group R⁴³, (vi) a group of the formula —CONR⁵⁷R⁵⁸, wherein R⁵⁷ andR⁵⁸ are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁵⁷and R⁵⁸ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, and wherein one of R⁵⁷ and R⁵⁸ may additionally be the group R⁴³,(vii) a group of the formula —COR⁵⁹, wherein R⁵⁹ is a hydrogen atom,straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5carbon atoms or R⁴³, (viii) a group of the formula —OR⁶⁰, wherein R⁶⁰ isa hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbonatoms, or R⁴³, (ix) a group of the formula —SR⁶¹, wherein R⁶¹ is ahydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbonatoms, or R⁴³, (x) cyano, (xi) nitro, or (xii) halogen,  R⁴¹ is:  arylselected from the class consisting of phenyl, 2-naphthyl, 2-, 3-, 5- or6-indolyl, 2- or 3-thiophenyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 4- or5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isothiazolyl, 4-or 5-oxadiazolyl, 1-, 4- or 5-triazolyl, 2-thiadiazolyl, 3- or4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3, 6- or 7-indolyzinyl,2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or 6-benzo[b]furanyl, 2-, 3-, 5-or 6-benzo[b]thiophenyl, 3-, 5- or 6-indazolyl, 2-, 5- or6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 3-, 6- or 7-quinolinyl,3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-, 3-, 7- or8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl, 2-, 3-, 6-or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or 7-pteridinyland 2-, 6- or 7-quinazolinyl,  wherein one or more of the hydrogen atomsof said aryl group may be optionally and independently replaced with:(A) R⁶², which is aryl selected from the class consisting of phenyl,2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl,2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl,3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl,2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3,6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-,3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-,3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl,2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or7-pteridinyl and 2-, 6- or 7-quinazolinyl,  wherein one or more of thehydrogen atoms of said aryl group may be optionally and independentlyreplaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atomsor cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group maybe mono- or polysubstituted with halogen or oxo, (ii) —COOH, (iii)—SO₂OH, (iv) —PO(OH)₂, (v) a group of the formula —COOR⁶³, wherein R⁶³is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3to 5 carbon atoms, (vi) a group of the formula —NR⁶⁴R⁶⁵, wherein R⁶⁴ andR⁶⁵ are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7carbon atoms, or wherein R⁶⁴ and R⁶⁵ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, (vii) a group of the formula—CONR⁶⁶R⁶⁷, wherein R⁶⁶ and R⁶⁷ are each, independently, a hydrogenatom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to6 carbon atoms, or wherein R⁶⁶ and R⁶⁷ constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom between them form a heterocyclic ring, (viii) a group ofthe formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom, or an alkyl,fluoroalkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of theformula —SR⁶⁹, wherein R⁶⁹ is a hydrogen atom, or an alkyl, fluoroalkylor acyl group of 1 to 7 carbon atoms, (x) cyano, (xi) nitro, or (xii) anamidino group of the formula

 wherein R⁷⁰, R⁷¹ and R⁷² are each, independently, a hydrogen atom oralkyl or fluoroalkyl of 1 to 3 carbon atoms, and wherein two of R⁷⁰, R⁷¹and R⁷² may additionally constitute a saturated hydrocarbon bridge of 3to 5 carbon atoms which together with the nitrogen atom(s) between themform a heterocyclic ring, or (xi) halogen, (B) methyl, which may bemono- or polysubstituted with fluorine atoms and additionally may bemonosubstituted with R⁶², (C) branched or unbranched alkyl of 2 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl orcycloakyl group may be mono- or polysubstituted with halogen or oxo, (D)a group of the formula —COOR⁷³, wherein R⁷³ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) agroup of the formula —NR⁷⁴R⁷⁵, wherein R⁷⁴ and R⁷⁵ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or wherein R⁷⁴ and R⁷⁵ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one of R⁷⁴ and R⁷⁵ may additionally bethe group R⁶², (F) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ andR⁷⁷ are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁷⁶and R⁷⁷ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, and wherein one of R⁷⁶ and R⁷⁷ may additionally be the group R⁶²,(G) a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom,straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5carbon atoms or R⁶², (H) a group of the formula —OR⁷⁹, wherein R⁷⁹ is ahydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbonatoms, or R⁶², (I) a group of the formula —SR⁸⁰, wherein R⁸⁰ is ahydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbonatoms, or R⁶², (J) cyano, (H) nitro, or (I) halogen; R⁴ is Cl ortrifluoromethyl; R⁵ is a hydrogen, fluorine, chlorine, bromine or iodineatom, methyl or trifluoromethyl; and, R⁶ is CN or NO₂; or apharmaceutically acceptable salt thereof.
 2. A compound of the formulaI, in accordance with claim 1, wherein: Y is an oxygen or sulfur atom; Zis an oxygen or sulfur atom; X is a divalent group of the formula >NR¹or >NSO₂R¹,  wherein R¹ is: (A) a hydrogen atom, (B) branched orunbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, which alkyl or cycloakyl group may be monosubstituted with: (i)halogen, (ii) oxo, (iii) aryl selected from the class consisting ofphenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl,pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl group may be optionallyand independently replaced with: (a) alkyl of 1 to 3 carbon atoms, (b)—COOH, (c) —SO₂OH, (d) —PO(OH)₂, (e) a group of the formula —COOR⁷,wherein R⁷ is straight or branched alkyl of 1 to 5 carbon atoms orcycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula —NR⁸R⁹,wherein R⁸ and R⁹ are each, independently, a hydrogen atom, alkyl of 1to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7carbon atoms, or wherein R⁸ and R⁹ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, (g) a group of the formula—CONR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are each, independently, a hydrogenatom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,or wherein R¹⁰ and R¹¹ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, (h) a group of the formula —OR^(12a), wherein R^(12a)is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,(i) a group of the formula —SR^(12b), wherein R^(12b) is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms, (j) cyano, or(k) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each, independently, a hydrogen atom oralkyl of 1 to 3 carbon atoms and wherein two of R¹³, R¹⁴ and R¹⁵ mayadditionally constitute a saturated hydrocarbon bridge of 3 to 5 carbonatoms which together with the nitrogen atom(s) between them form aheterocyclic ring, (iv) a group of the formula —COOR¹⁶, wherein R¹⁶ isstraight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to6 carbon atoms, (v) cyano, (vi) a group of the formula —CONR¹⁷R¹⁸,wherein R¹⁷ and R¹⁸ are each, independently, a hydrogen atom, alkyl of 1to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R¹⁷and R¹⁸ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, (vii) a group of the formula —OR¹⁹, wherein R¹⁹ is a hydrogenatom, or an alkyl or acyl group of 1 to 7 carbon atoms, (viii) a groupof the formula —SR²⁰, wherein R²⁰ is a hydrogen atom, or an alkyl oracyl group of 1 to 7 carbon atoms, (ix) a group of the formula —NR²¹R²²,wherein R²¹ and R²² are each, independently: (a) a hydrogen atom, (b)alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbonatoms, (c) a group of the formula —(CH₂)_(m)COOH, wherein m is 0, 1 or2, or (d) a group of the formula —(CH₂)_(n)COOR²³, wherein n is 0, 1 or2,  wherein R²³ is straight or branched alkyl of 1 to 6 carbon atoms, or wherein R²¹ and R²² constitute a saturated hydrocarbon bridge of 3to 5 carbon atoms which together with the nitrogen atom between themform a heterocyclic ring, or (x) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each, independently, a branched orunbranched alkyl group of 1 to 7 carbon atoms and Q⁻ is a chlorine,bromine or iodine counterion, (C) a branched or unbranched carboxylicacid group of 3 to 6 carbon atoms, (D) a branched or unbranchedphosphonic acid group of 2 to 6 carbon atoms, (E) a branched orunbranched sulfonic acid group of 2 to 6 carbon atoms, (F) an amidinogroup of the formula

 wherein r is 2, 3, 4, 5 or 6, and  R²⁷, R²⁸ and R²⁹ are each,independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms andwherein two of R²⁷, R²⁸ and R²⁹ may additionally constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom(s) between them form a heterocyclic ring, (G) an guanidinogroup of the formula

 wherein s is 2, 3, 4, 5 or 6, and  R³⁰, R³¹, R³² and R³³ are eachindependently a hydrogen atom or alkyl of 1 to 3 carbon atoms andwherein two of R³⁰, R³¹, R³² and R³³ may additionally constitute asaturated hydrocarbon bridge of 3 to 5 carbon atoms which together withthe nitrogen atom(s) between them form a heterocyclic ring, or (H)piperidyl, wherein the nitrogen atom of said group is optionallysubstituted with: (i) alkyl of 1 to 3 carbon atoms, (ii) a carboxylicester group of 2 to 7 carbon atoms, (iii) a carboxylic acid group of 2to 5 carbon atoms, (iv) a phosphonic acid group of 1 to 6 carbon atoms,or (v) a sulfonic acid group of 1 to 6 carbon atoms;  R² is: (A) ahydrogen atom, or (B) methyl; R³ is a group of the formula —CH₂R⁴¹,wherein:  R⁴¹ is:  aryl selected from the class consisting of phenyl,2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-, 3- or4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl,2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl,3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl,2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3,6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-,3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-,3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl,2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or7-pteridinyl and 2-, 6- or 7-quinazolinyl,  wherein one or more of thehydrogen atoms of said aryl group are necessarily and independentlyreplaced with: (A) R⁶², which is aryl selected from the class consistingof phenyl, 2-naphthyl, 2-, 3-, 5- or 6-indolyl, 2- or 3-thiophenyl, 2-,3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-furyl, 1-, 2- or3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-, 4- or5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4-or 5-isothiazolyl, 4- or 5-oxadiazolyl, 1-, 4- or 5-triazolyl,2-thiadiazolyl, 3- or 4-pyridazinyl, 2-pyrazinyl, 2-triazinyl, 2-, -3,6- or 7-indolyzinyl, 2-, 3-, 5- or 6-isoindolyl, 2-, 3-, 5- or6-benzo[b]furanyl, 2-, 3-, 5- or 6-benzo[b]thiophenyl, 3-, 5- or6-indazolyl, 2-, 5- or 6-benzthiazolyl, 2-, 5- or 6-benzimidazolyl, 2-,3-, 6- or 7-quinolinyl, 3-, 6- or 7-isoquinolinyl, 2- or 8-purinyl, 2-,3-, 7- or 8-quinolizinyl, 3-, 6- or 7-cinnolinyl, 6- or 7-pthalaninyl,2-, 3-, 6- or 7-quinoxalinyl, 2-, 3-, 6- or 7-napthyridinyl, 2-, 6- or7-pteridinyl and 2-, 6- or 7-quinazolinyl,  wherein one or more of thehydrogen atoms of said aryl group may be optionally and independentlyreplaced with: (i) branched or unbranched alkyl of 1 to 6 carbon atomsor cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group maybe mono- or polysubstituted with halogen or oxo, (ii) —COOH, (iii)—SO₂OH, (iv) —PO(OH)₂, (v) a group of the formula —COOR⁶³, wherein R⁶³is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3to 5 carbon atoms, (vi) a group of the formula —NR⁶⁴R⁶⁵, wherein R⁶⁴ andR⁶⁵ are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7carbon atoms, or wherein R⁶⁴ and R⁶⁵ constitute a saturated hydrocarbonbridge of 3 to 5 carbon atoms which together with the nitrogen atombetween them form a heterocyclic ring, (vii) a group of the formula—CONR⁶⁶R⁶⁷, wherein R⁶⁶ and R⁶⁷ are each, independently, a hydrogenatom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to6 carbon atoms, or wherein R⁶⁶ and R⁶⁷ constitute a saturatedhydrocarbon bridge of 3 to 5 carbon atoms which together with thenitrogen atom between them form a heterocyclic ring, (viii) a group ofthe formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom, or an alkyl,fluoroalkyl or acyl group of 1 to 7 carbon atoms, (ix) a group of theformula —SR⁶⁹, wherein R⁶⁹ is a hydrogen atom, or an alkyl, fluoroalkylor acyl group of 1 to 7 carbon atoms, (x) cyano, (xi) nitro, (xii) anamidino group of the formula

 wherein R⁷⁰, R⁷¹ and R⁷² are each, independently, a hydrogen atom oralkyl or fluoroalkyl of 1 to 3 carbon atoms, and wherein two of R⁷⁰, R⁷¹and R⁷² may additionally constitute a saturated hydrocarbon bridge of 3to 5 carbon atoms which together with the nitrogen atom(s) between themform a heterocyclic ring, or (xiii) halogen, (B) methyl, which may bemono- or polysubstituted with fluorine atoms and additionally may bemonosubstituted with R⁶², (C) branched or unbranched alkyl of 2 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl orcycloakyl group may be mono- or polysubstituted with halogen or oxo, (D)a group of the formula —COOR⁷³, wherein R⁷³ is straight or branchedalkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (E) agroup of the formula —NR⁷⁴R⁷⁵, wherein R⁷⁴ and R⁷⁵ are each,independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbonatoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms,or wherein R⁷⁴ and R⁷⁵ constitute a saturated hydrocarbon bridge of 3 to5 carbon atoms which together with the nitrogen atom between them form aheterocyclic ring, and wherein one of R⁷⁴ and R⁷⁵ may additionally bethe group R⁶², (F) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ andR⁷⁷ are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R⁷⁶and R⁷⁷ constitute a saturated hydrocarbon bridge of 3 to 5 carbon atomswhich together with the nitrogen atom between them form a heterocyclicring, and wherein one of R⁷⁶ and R⁷⁷ may additionally be the group R⁶²,(G) a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom,straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5carbon atoms or R⁶², (H) a group of the formula —OR⁷⁹, wherein R⁷⁹ is ahydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbonatoms, or R⁶², (I) a group of the formula —SR⁸⁰, wherein R⁸⁰ is ahydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbonatoms, or R⁶², (J) cyano, (K) nitro, or (L) halogen; R⁴ is Cl ortrifluoromethyl; R⁵ is a hydrogen, fluorine, chlorine, bromine or iodineatom, methyl or trifluoromethyl; and, R⁶ is CN or NO₂; or apharmaceutically acceptable salt thereof.
 3. A compound of the formulaI, in accordance with claim 1, wherein: Y is an oxygen atom; Z is anoxygen atom; X is a divalent group of the formula >NR¹,  wherein R¹ is:(A) a hydrogen atom, (B) branched or unbranched alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakylgroup may be monosubstituted with: (i) oxo, (ii) aryl selected from theclass consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl and triazinyl,  wherein one or more hydrogen atoms of saidaryl group may be optionally and independently replaced with: (a) alkylof 1 to 3 carbon atoms, (b) —COOH, (c) —SO₂OH, (d) —PO(OH)₂, (e) a groupof the formula —COOR⁷, wherein R⁷ is straight or branched alkyl of 1 to5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of theformula —NH₂, (g) a group of the formula —CONH₂, (h) a group of theformula —OR^(12a), wherein R^(12a) is a hydrogen atom or a methyl, (i)an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms, (j) a group of theformula —COOR¹⁶, wherein R¹⁶ is straight or branched alkyl of 1 to 7carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (k) a group of theformula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, or (l) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each methyl and Q⁻ is a chlorine, bromineor iodine counterion, (C) a branched or unbranched carboxylic acid groupof 3 to 6 carbon atoms, (D) a branched or unbranched phosphonic acidgroup of 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acidgroup of 2 to 6 carbon atoms, (F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and  R²⁷, R²⁸ and R²⁹ are each hydrogenatoms, (G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,  R³⁰, R³¹, R³² and R³³ are each hydrogenatoms, or (H) piperidyl, wherein the nitrogen atom of said group isoptionally substituted with: (i) alkyl of 1 to 3 carbon atoms, (ii) acarboxylic ester group of 2 to 7 carbon atoms, (iii) a carboxylic acidgroup of 2 to 5 carbon atoms, (iv) a phosphonic acid group of 1 to 6carbon atoms, or (v) a sulfonic acid group of 1 to 6 carbon atoms;  R²is: (A) a hydrogen atom, or (B) methyl; R³ is a group of the formula—CH₂R⁴¹, wherein  R⁴¹ is  aryl selected from the class consisting ofphenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl,thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl and triazinyl,  whereinone or more of the hydrogen atoms of said aryl group are necessarily andindependently replaced with: (A) R⁶², which is aryl selected from theclass consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl and triazinyl,  wherein one or more of the hydrogen atoms ofsaid aryl group may be optionally and independently replaced with: (i)methyl, (ii) —COOH, (iii) —SO₂OH, (iv) —PO(OH)₂, (v) a group of theformula —COOR⁶³, wherein R⁶³ is methyl, (vi) a group of the formula—NR⁶⁴R⁶⁵, wherein R⁶⁴ and R⁶⁵ are each, independently, a hydrogen atomor methyl, (vii) a group of the formula —CONR⁶⁶R⁶⁷, wherein R⁶⁶ and R⁶⁷are each, independently, a hydrogen atom or methyl, (viii) a group ofthe formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom or methyl, (ix) agroup of the formula —SR⁶⁹, wherein R⁶⁹ is a hydrogen atom or methyl,(x) cyano, (xi) nitro, or (xii) halogen, (B) methyl, which may be mono-or polysubstituted with fluorine atoms and which additionally may bemonosubstituted with R⁶², (C) branched or unbranched alkyl of 2 to 6carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl orcycloakyl group may be mono- or polysubstituted with halogen or oxo, (D)a group of the formula —COOR⁷³, wherein R⁷³ is methyl, (E) a group ofthe formula —NR⁷⁴R⁷⁵, wherein R⁷⁴ and R⁷⁵ are each, independently, ahydrogen atom or methyl, and wherein one of R⁷⁴ and R⁷⁵ may additionallybe the group R⁶², (F) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ andR⁷⁷ are each, independently, a hydrogen atom or methyl, and wherein oneof R⁷⁶ and R⁷⁷ may additionally be the group R⁶², (G) a group of theformula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom, methyl or R⁶², (H) agroup of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methyl orR⁶², (I) a group of the formula —SR⁸⁰, wherein R⁸⁰ is a hydrogen atom,methyl or R⁶², (J) cyano, (K) nitro, or (L) halogen; R⁴ is Cl ortrifluoromethyl; R⁵ is a hydrogen atom; and, R⁶ is CN or NO₂; or apharmaceutically acceptable salt thereof.
 4. A compound of the formulaI, in accordance with claim 1, wherein: Y is an oxygen atom; Z is anoxygen atom; X is a divalent group of the formula >NR¹,  wherein R¹ is:(A) a hydrogen atom, (B) branched or unbranched alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakylgroup may be monosubstituted with: (i) oxo, (ii) aryl selected from theclass consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl,pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrazinyl and triazinyl,  wherein one or more hydrogen atoms of saidaryl group may be optionally and independently replaced with: (a) alkylof 1 to 3 carbon atoms, (b) —COOH, (c) —SO₂OH, (d) —PO(OH)₂, (e) a groupof the formula —COOR⁷, wherein R⁷ is straight or branched alkyl of 1 to5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of theformula —NH₂, (g) a group of the formula —CONH₂, (h) a group of theformula —OR^(12a), wherein R^(12a) is a hydrogen atom or a methyl, (i)an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms, (j) a group of theformula —COOR¹⁶, wherein R¹⁶ is straight or branched alkyl of 1 to 7carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (k) a group of theformula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, or (l) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each methyl and Q⁻ is a chlorine, bromineor iodine counterion, (C) a branched or unbranched carboxylic acid groupof 3 to 6 carbon atoms, (D) a branched or unbranched phosphonic acidgroup of 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acidgroup of 2 to 6 carbon atoms, (F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and  R²⁷, R²⁸ and R²⁹ are each hydrogenatoms, (G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,  R³⁰, R³¹, R³² and R³³ are each hydrogenatoms, or (H) piperidyl, wherein the nitrogen atom of said group isoptionally substituted with: (i) alkyl of 1 to 3 carbon atoms, (ii) acarboxylic ester group of 2 to 7 carbon atoms, (iii) a carboxylic acidgroup of 2 to 5 carbon atoms, (iv) a phosphonic acid group of 1 to 6carbon atoms, or (v) a sulfonic acid group of 1 to 6 carbon atoms;  R²is: (A) a hydrogen atom, or (B) methyl; R³ is a group of the formula—CH₂R⁴¹, wherein  R⁴¹ is  aryl selected from the class consisting ofphenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, andpyrazinyl,  wherein one or more of the hydrogen atoms of said aryl groupare necessarily and independently replaced with: (A) R⁶², which is arylselected from the class consisting of phenyl, thiophenyl, pyridyl,pyrimidinyl, furyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, pyridazinyl, and pyrazinyl,  wherein one ormore of the hydrogen atoms of said aryl group may be optionally andindependently replaced with: (i) methyl, (ii) —COOH, (iii) a group ofthe formula —COOR⁶³, wherein R⁶³ is methyl, (iv) a group of the formula—OR⁶⁸, wherein R⁶⁸ is a hydrogen atom or methyl, or (v) halogen, (B)methyl, which may be mono- or polysubstituted with fluorine atoms orwhich may be monosubstituted with R⁶², (C) branched or unbranched alkylof 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkylor cycloakyl group may be mono- or polysubstituted with halogen or oxo,(D) a group of the formula —COOR⁷³, wherein R⁷³ is methyl, (E) a groupof the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ and R⁷⁷ are each methyl, andwherein one of R⁷⁶ and R⁷⁷ is methyl and the other is the group R⁶², (F)a group of the formula —COR⁷⁸, wherein R⁷⁸ is a hydrogen atom, methyl orR⁶², (G) a group of the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom,methyl or R⁶², (H) cyano, (I) nitro, or (J) halogen; R⁴ is Cl ortrifluoromethyl; R⁵ is a hydrogen atom; and, R⁶ is CN or NO₂; or apharmaceutically acceptable salt thereof.
 5. A compound of the formulaI, in accordance with claim 1, wherein: Y is an oxygen atom; Z is anoxygen atom; X is a divalent group of the formula >NR¹, wherein R¹ is:(A) a hydrogen atom, (B) branched or unbranched alkyl of 1 to 6 carbonatoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakylgroup may be monosubstituted with: (i) oxo, (ii) aryl selected from theclass consisting of phenyl or pyridyl,  wherein one or more hydrogenatoms of said aryl group may be optionally and independently replacedwith: (a) alkyl of 1 to 3 carbon atoms, (b) —COOH, (c) —SO₂OH, (d)—PO(OH)₂, (e) a group of the formula —OR^(12a), wherein R^(12a) is ahydrogen atom or a methyl, (f) an amidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms, (iii) a group of theformula —OR¹⁹, wherein R¹⁹ is a hydrogen atom, or an alkyl or acyl groupof 1 to 7 carbon atoms, or (iv) a quaternary group of the formula

 wherein R²⁴, R²⁵ and R²⁶ are each methyl and Q⁻ is a chlorine, bromineor iodine counterion, (C) a branched or unbranched carboxylic acid groupof 3 to 6 carbon atoms, (D) a branched or unbranched phosphonic acidgroup of 2 to 6 carbon atoms, (E) a branched or unbranched sulfonic acidgroup of 2 to 6 carbon atoms, (F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and  R²⁷, R²⁸ and R²⁹ are each hydrogenatoms, (G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,  R³⁰, R³¹, R³² and R³³ are each hydrogenatoms, or (H) piperidyl, wherein the nitrogen atom of said group isoptionally substituted with: (i) alkyl of 1 to 3 carbon atoms, (ii) acarboxylic ester group of 2 to 7 carbon atoms, (iii) a carboxylic acidgroup of 2 to 5 carbon atoms, (iv) a phosphonic acid group of 1 to 6carbon atoms, or (v) a sulfonic acid group of 1 to 6 carbon atoms;  R²is: (A) a hydrogen atom, or (B) methyl; R³ is a group of the formula—CH₂R⁴¹, wherein  R⁴¹ is  aryl selected from the class consisting ofphenyl or pyridyl,  wherein one or more of the hydrogen atoms of saidaryl group are necessarily and independently replaced with: (A) R⁶²,which is aryl selected from the class consisting of phenyl, or pyridyl, wherein one or more of the hydrogen atoms of said aryl group may beoptionally and independently replaced with: (i) methyl, (ii) —COOH (iii)a group of the formula —COOR⁶³, wherein R⁶³ is methyl, (iv) a group ofthe formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom or methyl, or (v)halogen, (B) methyl, which may be mono- or polysubstituted with fluorineatoms or which may be monosubstituted with R⁶², (C) branched orunbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbonatoms, which alkyl or cycloakyl group may be mono- or polysubstitutedwith fluorine or oxo, (D) a group of the formula —COOR⁷³, wherein R⁷³ ismethyl, (E) a group of the formula —CONR⁷⁶R⁷⁷, wherein R⁷⁶ and R⁷⁷ areeach methyl, and wherein one of R⁷⁶ and R⁷⁷ is methyl and the other isthe group R⁶², (F) a group of the formula —COR⁷⁸, wherein R⁷⁸ is ahydrogen atom, methyl or R⁶², (G) a group of the formula —OR⁷⁹, whereinR⁷⁹ is a hydrogen atom, methyl or R⁶², (H) cyano, (I) nitro, or (J)halogen; R⁴ is Cl or trifluoromethyl; R⁵ is a hydrogen atom; and, R⁶ isCN or NO₂; or a pharmaceutically acceptable salt thereof.
 6. A compoundof the formula I, in accordance with claim 1, wherein: Y is an oxygenatom; Z is an oxygen atom; X is a divalent group of the formula >NR¹, R¹ is: (A) a hydrogen atom, (B) alkyl of 1 to 2 carbon atoms which maybe monosubstituted with: (i) oxo, (ii) aryl selected from the classconsisting of phenyl or pyridyl,  wherein one hydrogen atom of said arylgroup may be optionally replaced with: (a) alkyl of 1 to 3 carbon atoms,(b) —COOH, (c) —SO₂OH, (d) —PO(OH)₂, (e) a group of the formula—OR^(12a), wherein R^(12a) is a hydrogen atom or a methyl, or (f) anamidino group of the formula

 wherein R¹³, R¹⁴ and R¹⁵ are each hydrogen atoms, or (iii) a group ofthe formula —OR¹⁹, wherein R¹⁹ is a hydrogen atom or methyl, (C) abranched or unbranched carboxylic acid group of 3 to 6 carbon atoms, (D)a branched or unbranched phosphonic acid group of 2 to 6 carbon atoms,(E) a branched or unbranched sulfonic acid group of 2 to 6 carbon atoms,(F) an amidino group of the formula

 wherein r is 2, 3, 4, 5 or 6, and  R²⁷, R²⁸ and R²⁹ are each hydrogenatoms, or (G) an guanidino group of the formula

 wherein s is 2, 3, 4, 5 or 6,  R³⁰, R³¹, R³² and R³³ are each hydrogenatoms,  R² is: (A) a hydrogen atom, or (B) methyl; R³ is a group of theformula —CH₂R⁴¹, wherein  R⁴¹ is  phenyl  wherein one or more of thehydrogen atoms of said phenyl group are necessarily and independentlyreplaced with: (A) R⁶², which is aryl selected from the class consistingof phenyl, or pyridyl,  wherein one or more of the hydrogen atoms ofsaid aryl group may be optionally and independently replaced with: (i)methyl, (ii) a group of the formula —COOR⁶³, wherein R⁶³ is methyl,(iii) a group of the formula —OR⁶⁸, wherein R⁶⁸ is a hydrogen atom ormethyl, or (iv) halogen, (B) methyl, which may be mono- orpolysubstituted with fluorine atoms or which may be monosubstituted withR⁶², (C) a group of the formula —COOR⁷³, wherein R⁷³ is methyl, (D) agroup of the formula —COR⁷⁸, wherein R⁷⁸ is methyl or R⁶², (E) a groupof the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methyl or R⁶², (F)cyano, (G) nitro, or (H) halogen; R⁴ is Cl or trifluoromethyl; R⁵ is ahydrogen atom; and, R⁶ is CN or NO₂; or a pharmaceutically acceptablesalt thereof.
 7. A compound of the formula I, in accordance with claim1, wherein: Y is an oxygen atom; Z is an oxygen atom; X is a divalentgroup of the formula >NR¹,  R¹ is: (A) a hydrogen atom, (B) methyl orethyl, or (C) —COCH₃  R² is: (A) a hydrogen atom, or (B) methyl; R³ is agroup of the formula —CH₂R⁴¹, wherein  R⁴¹ is  phenyl  wherein one ormore of the hydrogen atoms of said phenyl group are necessarily andindependently replaced with: (A) R⁶², which is aryl selected from theclass consisting of phenyl, or pyridyl,  wherein one or more of thehydrogen atoms of said aryl group may be optionally and independentlyreplaced with: (i) methyl, (ii) a group of the formula —COOR⁶³, whereinR⁶³ is methyl, (iii) a group of the formula —OR⁶⁸, wherein R⁶⁸ is ahydrogen atom or methyl, or (iv) halogen, (B) methyl, which may be mono-or polysubstituted with fluorine atoms or which may be monosubstitutedwith R⁶², (C) a group of the formula —COOR⁷³, wherein R⁷³ is methyl, (D)a group of the formula —COR⁷⁸, wherein R⁷⁸ is methyl or R⁶², (E) a groupof the formula —OR⁷⁹, wherein R⁷⁹ is a hydrogen atom, methyl or R⁶², (F)cyano, (G) nitro, or (H) halogen; R⁴ is Cl or trifluoromethyl; R⁵ is ahydrogen atom; and, R⁶ is CN or NO₂; or a pharmaceutically acceptablesalt thereof.
 8. A compound of the formula I, in accordance with claim1, wherein: Y is an oxygen atom; Z is an oxygen atom; X is a divalentgroup of the formula >NR¹,  R¹ is: (A) a hydrogen atom, (B) methyl orethyl, or (C) —COCH₃  R² is: (A) a hydrogen atom, or (B) methyl; R³ is agroup of the formula —CH₂R⁴¹, wherein  R⁴¹ is  phenyl  wherein one ormore of the hydrogen atoms of said phenyl group are necessarily andindependently replaced with: (A) R⁶², which is aryl selected from theclass consisting of phenyl, or pyridyl,  wherein one or more of thehydrogen atoms of said aryl group may be optionally and independentlyreplaced with: (i) methyl, or (ii) halogen, (B) methyl, which may bemono- or polysubstituted with fluorine atoms, (C) a group of the formula—COR⁷⁸, wherein R⁷⁸ is methyl or R⁶², (D) halogen; R⁴ is a chlorineatom; R⁵ is a hydrogen atom; and, R⁶ is CN or NO₂; or a pharmaceuticallyacceptable salt thereof.
 9. A compound of the formula I, in accordancewith claim 1, selected from the group consisting of:5-(R)-(4-bromobenzyl)-3-(3-chloro-5-nitrophenyl)-5-methylimidazoline-2,4-dione;and,5-(R)-(4-bromobenzyl)-3-(3-chloro-5-cyanophenyl)-5-methylimidazoline-2,4-dione;or a pharmaceutically acceptable salt thereof.
 10. A compound of theformula I, in accordance with claim 1, 2, 3, 4, 5, 6, 7, 8, or 9 havingthe absolute stereochemistry depicted below in formula Ia:


11. A pharmaceutical composition comprising a pharmaceuticallyacceptable adjuvant or carrier and a compound of the formula I, inaccordance with claim 1, 2, 3, 4, 5, 6, 7, 8, or
 9. 12. A method for thetreatment of inflammatory or immune cell-mediated diseases whichcomprises administering to a host in need of such treatment atherapeutic amount of a compound of the formula I in accordance withclaim 1, 2, 3, 4, 5, 6, 7, 8, or
 9. 13. The method of claim 12 whereinthe disease or condition is selected from the group consisting of adultrespiratory distress syndrome, shock, multiple organ injury syndromesecondary to septicemia, multiple organ injury syndrome secondary totrauma, reperfusion injury of tissue due to cardiopulmonary bypass,myocardial infarction or use with thrombolysis agents, acuteglomerulonephritis, vasculitis, reactive arthritis, dermatosis withacute inflammatory components, stroke, thermal injury, hemodialysis,leukapheresis, ulcerative colitis, necrotizing enterocolitis andgranulocyte transfusion associated syndrome.
 14. The method of claim 12wherein the disease or condition is selected from the group consistingof psoriasis, organ/tissue transplant rejection, graft vs. hostreactions and autoimmune diseases including Raynaud's syndrome,autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoidarthritis, insulin-dependent diabetes mellitus, uveitis, inflammatorybowel disease including Crohn's disease and ulcerative colitis, andsystemic lupus erythematosus.
 15. The method of claim 12 wherein thedisease or condition is asthma.